This GO grant addresses the critical need for development of biosensors that detect protein dysfunction during aging. The long-term health of all cells is inextricably linked to protein folding and sustainability of function. This is achieved by protein homeostatasis or 'proteostasis'(Balch et al. (2008) Science 319: 916), a complex network of molecular interactions that determines the health of the proteome. Proteostasis balances protein biosynthesis, folding, translocation, assembly/disassembly and clearance with the challenges imposed by environmental or physiological stress that results in a continual flux of misfolded and damaged proteins that the cell must manage. An imbalance, if left unattended can result in severe molecular damage to the cell, dysregulation of key tissues leading to pathology, and susceptibility to nearly all of diseases of aging. Adaptation and survival requires an ability to sense these damaged proteins and to coordinate induction of protective stress response pathways, chaperone and clearance networks. Despite the abundance and apparent capacity of the proteostasis network to restore the folding equilibrium, the cell appears to be poorly adapted for chronic proteotoxic stress as occurs when certain aggregation-prone proteins are expressed, for instance, in neurodegenerative aging diseases. We have hypothesized that this decline in repair activities, that challenges the integrity of the proteome, is influenced strongly by genes that control aging- thus linking stress biology, metabolism (diet), and protein homeostasis with health and human lifespan. The proposal brings together the complementary strengths of the Balch, Kelly and Wiseman laboratories at The Scripps Research Institute, the Dillin laboratory at the Salk Institute and the Morimoto laboratory at Northwestern University, to develop and test a new set of molecular tools that will globally report on the health of the proteome during aging. These groups form the Proteostasis Aging Sensor Consortium (PASC) to develop 'proteostasis sensors", innovative molecular reporters that will provide real- time assessment of the capabilities of protein folding quality control in each compartment of the cell, and in tissue and organismal models. These innovative probes will assess the consequences of protein damage, cell stress, aging and diseases of protein conformation that influence human longevity. The impact of these studies on the aging field is very broad and extends across all areas of biology and medicine. The combined collaborative efforts from the members of the PASC will leverage the tools, techniques and knowledge of protein homeostasis and aging to gauge the folding environment within cells and animals, and provide the next generation tools that will considerably accelerate efforts in the aging sciences. PUBLIC HEALTH RELEVANCE: The long-term health of mankind during aging is inextricably linked to protein folding and sustainability of protein function in spite of the many challenges imposed by environmental and/or physiological stress. Longevity requires an ability to sense damaged proteins and to coordinate induction of protective pathways and clearance networks responsive to genes that control aging, stress biology and metabolism (diet). This proposal by the Proteostasis Aging Sensor Consortium (PASC) consisting of the Balch-Dillin-Kelly-Morimoto- Wiseman groups will develop and test a new set of innovative molecular tools, referred to as proteostasis sensors that will globally report in real-time on the health of the human proteome during aging. The impact of these studies on the aging field is necessarily very broad and extends across all areas of biology and medicine related to human health.